Goblet cell adenocarcinoma of the anal canal with perianal Paget disease: A rare case report with literature review

Introduction: AS an uncommon neoplasm, goblet cell adenocarcinoma (GCA) is characterized by mixed endocrine-exocrine features. It is almost exclusively found in the appendix. Primary GCA of the anal canal is extremely rare. Case presentation: Herein we describe a novel rare case of 74-year-old Chinese female who is diagnosed with GCA in the anal canal with perianal Paget disease, including a brief review of the literature. In the lesion of anal canal, the tumor was composed of signet-ring-like cells on confluent growth model and copious mucin was produced as well. Simultaneously, the results of immunohistochemistry showed signet-ring-like cells were positive for CK20, CDX2, synaptophysin (Syn), CD56, carcinoembryonic antigen (CEA) and Villin. Meanwhile, the Ki67-labeling index reached 40%. In the lesion of perianal Paget disease, the small groups of atypical neoplastic cells were present in the epidermis. Immunohistochemically, the neoplastic cells were positive for CK20, CDX2 and epithelial membrane antigen, but negative for CK7, GCDFP15, S100, HMB45, and P63. The Ki67-labeling index reached 60% in the most concentrated spot. Conclusions: Extra-appendiceal GCA was rare and easily under-recognizable. The diagnosis of GCA was seldom made preoperatively. Occasionally, GCA could occur in the anal canal accompanied by perianal Paget disease. So careful rectal examination was important in the patient with perianal Paget disease for avoid missing diagnosis of GCA on anal canal. GCA may show aggressive clinical behavior compared with typical well-differentiated neuroendocrine tumors. Therefore, we should pay more attention on the recognization of this rare disease.


Introduction
Goblet cell adenocarcinoma (GCA) is predominantly composed of goblet cells. Occasionally, neuroendocrine cells and Paneth cells are also present. The cells often arrange in small tubules, which is similar to intestinal crypts. Typically, the tumor cells show very little cytologic atypia and mitotic figures are rare as well. Both neuroendocrine granules and mucin droplets are present in the same cells, meanwhile, the tumor cells are positive for epithelial markers and neuroendocrine markers, resulting in the origin of cell has historically been elusive. So the nomenclature and classification of GCA have been the subject of debate for a long time. In 1969, the authors first described these tumors, pointing out that they represented a class of tumors with features intermediate between adenocarcinomas and digestive tract carcinoids. [1] Subsequently, many different names were introduced for these tumors, including Mucinous carcinoid tumor, goblet cell carcinoid, well-differentiated adenocarcinoma adenocarcinoid, crypt cell carcinoma, adenocarcinoma ex-goblet cell carcinoid, and mixed adenoneuroendocrine carcinoma. [2] Until recently, the WHO classificatory system claimed that these tumors should not be considered as a variant of neuroendocrine tumors. They were more appropriately grouped with other adenocarcinomas in terms of their behavior and biology. In 2019, GCA was formally recommended by World Health Organization.
Appendix is the most common site for GCA though extra-appendix sites, such as the duodenum, bronchus, stomach, biliary tract, small intestine and colon, have also been reported. [1,[3][4][5][6] Compared to appendiceal GCA, GCA in the lower gastrointestinal tract is exceedingly rare. There are only rare cases was reported about the GCA of rectum and its etiology is still unclear. [4,[7][8][9][10][11][12][13][14] Our study gave a detailed account of the first case of anal GCA accompanied with perianal Paget disease encountered in a 74-year-old female.

Case presentation
A 74-year-old Chinese woman consulted her local physician about she has a history of perianal pruritus and hematochezia for nearly a month. So she was admitted to our hospital for investigations and treatment. At physical examination, eczematous plaque with white scaling and ulcerations was found on the left side of the anus, which measured about 5 × 3 cm. On digital rectal examination, a hard tumor was palpable on the left anterior wall of the anal canal, which measured about 1 cm in radius. Prior to this presentation, she did not have history of acute appendicitis. No lymph node metastasis or remote metastatic lesions were found on the computed tomography scan. Laboratory tests showed almost all of the tumor markers were normal and colonoscopic examination did not show any abnormalities. Subsequently, histological examination of biopsies was performed on the perianal skin and anal canal. The diagnosis of GCA in the anal canal with perianal Paget disease was made. About a week later, Miles' operation with lymph node dissection was performed. After the surgery, several chemotherapy regimens were given and the patient was stable for 24 months.
Histological examination of the anal canal revealed an invasive lesion in submucosal and muscular layer, which mainly in the anal canal but focally invading the lower rectum ( Fig. 1A-C). The tumor was composed of signet-ring-like cells on confluent growth model and copious mucin was produced as well (Fig. 1D). Focally, the vessel invasion was found as well ( Fig. 1E). Peripheral to the normal anal glands, we found individual adenocarcinoma in situ (Fig. 1F). Unfortunately, the transition between the confluent nest of signet-ringlike cells and Paget disease in the epidermis was not found. Simultaneously, the results of immunohistochemistry showed signet-ring-like cells were positive for Syn, CD56, CDX2, CEA, Villin, and cytokeratin (CK) 20 ( Fig. 2A, B, D-G). However, Negative staining for chromogranin A was shown (Fig. 2C). The Ki67-labeling index reached 40% in the most concentrated spot (Fig. 2H). Therefore, we made a diagnosis of GCA in this patient.
Meanwhile, on the lesion of perianal Paget disease, the result showed isolated/small groups of atypical neoplastic cells were present in the epidermis without dermal invasion (Fig. 3A). The cells showed pale clear cytoplasm and large hyperchromatic nuclei (Fig. 3B). Focally, the hair follicle was involved by the tumor cells (Fig. 3C). Immunohistochemically, the neoplastic cells were positive for CK20, CDX2 and epithelial membrane antigen ( Fig. 3D-F) but negative for CK7, GCDFP15, S100, HMB45, and P63 (Fig. 3G). The Ki67-labeling index reached 60% in the most concentrated spot (Fig. 3H). Therefore, we made a diagnosis of Paget disease in this patient.

Discussion
The gastrointestinal epithelium consist of various different kinds of cells, each kind of cells carries out specialized functions. Among these cells, there is Paneth cells that release antimicrobial factors, entero-endocrine cells that play a important role in secreting hormones and goblet cells which are responsible for secrete mucins. [1] Beside barrier maintenance function of the mucins, the goblet cells also secrete chemokines, cytokines and anti-microbial proteins which play a key role in innate immunity. [15] As far as we all know, goblet cells was usually found in the reproductive system, conjunctiva, respiratory tract and gastrointestinal tracts, and other columnar epithelial cells often surround them. [15,16] GCA was first described by Gagne in 1969. [1] As a rare disease process, GCA was mainly found in appendix, which can present with acute appendicitis, chronic abdominal pain, or no symptoms at all. [17] Primary extra-appendiceal GCA, such as stomach, duodenum, ampulla of Vater, jejunum, ileum, cecum, splenic flexure and ascending colon, was extremely rare. [1,[3][4][5][6] To date, only 10 cases was reported about the GCA of rectum through literature review (Table 3). Our study gave a detailed account of an extremely rare case of anal canal GCA, which mainly in the anal canal but focally invading the lower rectum. Meanwhile, it was accompanied by perianal Paget disease. To date, no similar case was reported. From Table 3, we found the median age at diagnosis of GCA in rectum or anal canal is 64 years. Most of them showed good prognosis by surgical operation with adjuvant chemotherapy. However, a few of them showed recurrence or remote metastasis, which resulting in poor prognosis.
GCA was previously known as goblet cell carcinoid (GCC) or adenocarcinoid, as it was characterized with mixed phenotype of dual neuroendocrine and glandular differentiation. Its clinical behavior could range from relatively indolent disease that are completely cured by excision to malignant disease that spread widely and even cause death. [18,19] The appendicular GCA was more aggressive compared with typical well-differentiated neuroendocrine tumors of the appendix but less aggressive compared with adenocarcinomas. For this reason, goblet cell carcinoid has been regarded as a distinctive entity, and is classified and staged as appendiceal adenocarcinomas. [17] In 2019 World Health Table 1 Summary of primary antibodies and results of immunohistochemistry in GCA.    Organization, GCA became the preferred terminology for this appendiceal tumor. [20] In our present case, the tumor was composed of signet-ring-like cells on confluent growth model and copious mucin was produced as well. Meanwhile, the tumor cells were positive for Syn, CD56, CDX2, CEA, Villin, and CK 20, further confirming its dual neuroendocrine and glandular differentiation. GCA had an incidence of approximately 0.12 cases per 1 million individuals per year. [21,22] Appendiceal GCC was reported in  approximately 14% to 19% of primary appendiceal cancers. [23] The median age at diagnosis was 58 years and there was no significant difference between males and females. [23] To date, no specific risk factors have been identified although rare cases of GCA have been associated with schistosomiasis. [24] Our report found the anal canal GCA was accompanied by perianal Paget disease, hinting it was possible that Paget disease was related to GCA. So careful digital rectal examination was important in the patient with perianal Paget disease for avoid missing diagnosis of GCA on anal canal.

Antibody
The characteristic pathological findings of GCA included goblet cell morphology with rich intracytoplasmic mucin and a small compressed nucleus, and concentric infiltration of the appendiceal wall by small tight clusters, cords, or nests of tumor cells. [25] The 3 tier grading systems of GCA was based on the proportion of goblet-like mucinous cells. Presence of at least 75% low grade pattern (tubular/nested architecture) was required for qualification of a tumor as grade 1, while grade 3 tumors should contain >50% high grade pattern (complex cribriform sheet-like growth pattern and/or single mucinous or non-mucinous cells). [20] In our case, confluent growth model or complex cribriform sheet-like growth pattern was showed, so it was grade 3 according to the grading systems. Focally, the vessel invasion was found in this case, revealed the possibility of the poor prognosis in grade 3.
The derivation of GCA was still unclear. Some report revealed the GCA was derived from undifferentiated stem cells, which was different from typical carcinoids that originate from Kulchitsky in the mucosal stroma. [26] The 2019 WHO classification, primary anal adenocarcinoma was divided into 2 subtypes: mucosal origin (arising from the luminal mucosa) and extramucosal origin (arising from anal glands, an anal fistula or non-fistulating glandular structures). [20] Peripheral to the normal anal glands, we found individual adenocarcinoma in situ, hinting GCA maybe originate from anal glands. However, large number of investigation are needed for confirming this hypothesis in the future.

Conclusions
In a conclusion, goblet cell tumors was rare and easily under-recognizable, especially occurred in extra-appendiceal lesion. Careful digital rectal examination was important in the patient with perianal Paget disease for avoid missing diagnosis of GCA on anal canal. Some of them may show aggressive clinical behavior. Therefore, we should pay more attention on the recognization of this rare disease.